Celtrix Pharmaceuticals, Inc.

Collagen Corporation

The United States of America As Represented by the Secretary of

Yasushi Ogawa

David K Schmidt

George A Ksander

George H Chu

John M McPherson

Diana M Hendricks

Hugh McMullin

Bruce Pratt

Rosa Armstrong

Ranga Nathan

Andrea Y Thompson

Saeid M Seyedin

Andreas Sommer

James R Dasch

David Passmore

Stephen Danko

Karl Piez

Sun Daopin

Peggy Tao

David R Davies

New pharmaceutical formulations for IGF/IGFBP complex are disclosed. IGF/IGFBP complex, preferably rhIGF-I/IGFBP-3 complex is formulated with bulking agents and optionally buffer salts, but without added osmolyte salts. Also disclosed are lyophilized formulations for IGF/IGFBP complex.

Pharmaceutical formulations for IGF/IGFBP

The present invention provides a novel method for refolding insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3(IGFBP-3). The method involves mixing of IGF-I and IGFBP-3 together in a cofolding reaction. The inventive cofolding method results in substantially higher yields of correctly folded protein for both molecules and alters the kinetics of refolding. The method includes the production of correctly folded IGF-I, IGFBP-3, and/or IGF-I/IGFBP-3 complex.

Method of producing insulin-like growth factor-I (IGF-I) and

The invention relates to peptides corresponding to regions of the amino acid sequence of TGF-.beta.1 or TGF-.beta.2 which retain, either in monomeric or polymeric forms, at least some of the biological activity of the respective full length TGF-.beta.. The monomeric form of the peptide derived from TGF-.beta.1 comprises the following amino acid sequence: CVRQLYIDFRKDLGWKWIHEPKGYHANFCLGP (SEQ ID NO: 1). The monomeric form of the peptide derived from TGF-.beta.2 comprises the following amino acid sequence: CLRPLYIDFKRDLGWKWIHEPKGYNANFCAGA (SEQ ID NO: 2). Dimers may be formed via disulfide bonds between the amino-terminal cysteine residues, the carboxy-terminal cysteine residues, or amino- and carboxy-terminal cysteine residues of the monomer subunits.

Biologically active TGF-.beta.1 peptides

A heterodimeric form of TGF-.beta. is described. This 25 KD molecule is active in an in vitro assay of inhibition of epithelial cell growth. The protein may be isolated from bone. When reduced, the protein elutes in two peaks by RP-HPLC. In immunoblots, the reduced protein from the earlier eluting peak reacts predominately with antibodies directed against TGF-.beta.3, while reduced protein from the later eluting peak reacts predominately with antibodies directed against TGF-.beta.2. The N-terminal amino acid sequence and immunoreactivity of the native protein are consistent with a heterodimer of TGF-.beta.2 and TGF-.beta.3.

Transforming growth factor .beta.2,3

Biologically active TGF-.beta.2 peptides

Activin is administered systemically and locally to induce the growth of mature bone. Activin enhances the level of bone formation and the quality of the bone formed when administered locally with BMP or bone marrow. Administration of activin by subcutaneous route promotes systemic increase in the bone mass.

Method and activin compositions for inducing bone growth

A composition of crystalline TGF-.beta.2 is described. The tertiary structure of the protein homodimer determined by X-ray crystallography to 2.1 angstrom resolution is shown. This structure provides data useful in the rational design of drugs to mimic the physiologic properties of proteins of the TGF-.beta. family.

Crystal structure of TGF-.beta.-2

Collagen implants that are useful as wound healing matrices are characterized by being formed of collagen fibrils that are not chemically cross-linked, and having a bulk density of 0.01 to 0.3 g/cm.sup.3 and a pore population in which at least about 80% of the pores have an average pore size of 35 to 250 microns. The implants are capable of promoting connective tissue deposition, angiogenesis, reepithelialization, and fibroplasia. The wound healing matrix also serves as an effective sustained delivery system for bioactive agents.

Collagen wound healing matrices and process for their production

Method for inducing bone growth

Processes for producing collagen matrixes and methods of using same

Collagen implants that are useful as wound healing matrices are characterized by being formed of collagen fibrils that are not chemically cross-linked, and having a bulk density of 0.01 to 0.3 g/cm.sup.3 and a pore population in which at least about 80% of the pores have an average pore size of 35 to 250 microns. The implants are capable of promoting connective tissue deposition, angiogenesis, reepithelialization, and fibroplasia. The wound healing matrix also serves an an effective sustained delivery system for synergistic combinations of FGF and TGF-B.

Growing community of inventors

Pacifica, CA, United States of America

Yasushi Ogawa